Somatic Mutations in Exocrine Pancreatic Tumors: Association with Patient Survival

KRAS mutations are major factors involved in initiation and maintenance of pancreatic tumors. The impact of different mutations on patient survival has not been clearly defined. We screened tumors from 171 pancreatic cancer patients for mutations in KRAS and CDKN2A genes. Mutations in KRAS were detected in 134 tumors, with 131 in codon 12 and only 3 in codon 61. The GGT>GAT (G12D) was the most frequent mutation and was present in 60% (80/134). Deletions and mutations in CDKN2A were detected in 43 tumors. Analysis showed that KRAS mutations were associated with reduced patient survival in both malignant exocrine and ductal adenocarcinomas (PDAC). Patients with PDACs that had KRAS mutations showed a median survival of 17 months compared to 30 months for those without mutations (log-rank P = 0.07) with a multivariate hazard ratio (HR) of 2.19 (95%CI 1.09–4.42). The patients with G12D mutation showed a median survival of 16 months (log-rank-test P = 0.03) and an associated multivariate HR 2.42 (95%CI 1.14–2.67). Although, the association of survival in PDAC patients with CDKN2A aberrations in tumors was not statistically significant, the sub-group of patients with concomitant KRAS mutations and CDKN2A alterations in tumors were associated with a median survival of 13.5 months compared to 22 months without mutation (log-rank-test P = 0.02) and a corresponding HR of 3.07 (95%CI 1.33–7.10). Our results are indicative of an association between mutational status and survival in PDAC patients, which if confirmed in subsequent studies can have potential clinical application.KRAS突变是参与胰腺肿瘤发生与维持的关键因素。目前不同KRAS突变亚型对患者生存的影响尚未明确阐明。本研究对171例胰腺癌患者的肿瘤组织开展KRAS及细胞周期蛋白依赖性激酶抑制剂2A（CDKN2A）基因的突变筛查。134例肿瘤组织检出KRAS突变，其中131例位于12号密码子，仅3例位于61号密码子。GGT>GAT（G12D）为最常见的突变类型，占比达60%（80/134）。43例肿瘤组织检出CDKN2A基因缺失与突变。分析结果显示，在恶性外分泌型胰腺肿瘤及胰腺导管腺癌（PDAC）患者中，KRAS突变均与患者生存期缩短相关。携带KRAS突变的PDAC患者中位生存期为17个月，而未携带该突变的患者中位生存期为30个月（对数秩检验P=0.07）；多因素分析显示其风险比（HR, Hazard Ratio）为2.19（95%置信区间CI: 1.09–4.42）。携带G12D突变的患者中位生存期为16个月（对数秩检验P=0.03），多因素分析对应的HR为2.42（95%CI: 1.14–2.67）。尽管PDAC患者肿瘤组织中CDKN2A异常与患者生存期的关联未达到统计学显著性，但同时携带KRAS突变与CDKN2A改变的患者亚组中位生存期仅为13.5个月，而未携带这两类异常的患者中位生存期为22个月（对数秩检验P=0.02），对应的多因素HR为3.07（95%CI:1.33–7.10）。本研究结果提示PDAC患者的突变状态与生存期存在关联，若后续研究得以验证，该发现有望具备潜在临床应用价值。